Limb girdle muscular dystrophy 2B (LGMD) and Miyoshi myopathy (MM) are both characterized by autosomal recessive inheritance, adult onset, and marked elevations of the muscle enzyme creatine kinase (Bushby, 1999, Brain 122:1403–1420). Both have been shown to arise from defects in a gene that encodes dysferlin (Bashir et al., 1998, Nat. Genet. 20:37–42; Liu et al., 1998, Nat. Genet. 20:31–36). The same mutation in the dysferlin gene can cause different clinical presentations, even among members of the same family (Illarioshkin et al., 2000, Neurology 55:1931–1933; Weiler et al., 1999, Hum. Mol. Genet. 8:871–877; Weiler et al., 1996, Am. J. Hum. Genet. 59:872–878). In addition, an anterior distal myopathy has been linked to a dysferlin mutation (Illa et al., 2001, Ann. Neurol. 49:130–134). Thus, there is considerable clinical heterogeneity among dysferlinopathies.
The dysferlin gene is large, comprising 55 exons that span a genomic region of over 150 kb (Aoki et al., 2001, Neurology 57:271–278). It encodes a membrane-associated 237 kDa dysferlin protein composed of 2,080 amino acids that is membrane-associated (Anderson et al., 1999, Hum. Mol. Genet. 8:855–861; Matsuda et al., 1999, Neurology 53:1119–1122; Selcen et al., 2001, Neurology 56:1472–81).
At present, an accurate diagnosis of dysferlinopathy requires a combination of clinical evaluation, protein studies (immunoblot or immunohistochemical analysis) of muscle tissue, and/or direct gene analysis. Moreover, defects in the dysferlin gene are predominantly single nucleotide changes with no evidence of recurrent mutations, gross rearrangements, or mutational hotspots to aid detection (Liu et al., 1998, Nat. Genet. 20:31–36; Aoki et al., 2001, Neurology 57:271–278; Anderson et al., 1999, Hum. Mol. Genet. 8:855–861). For these reasons, DNA-based diagnosis is difficult to use as an initial screening strategy to distinguish dysferlinopathies from the other forms of muscular dystrophy.